US2025276063A1PendingUtilityA1

Placenta-dervied nk cells as a senol ytic for therapeutic and other uses

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Assignee: CELULARITY INCPriority: Jul 29, 2021Filed: Jul 29, 2022Published: Sep 4, 2025
Est. expiryJul 29, 2041(~15 yrs left)· nominal 20-yr term from priority
Inventors:William Van Der TouwRobert J. HaririTanel Mahlakoiv
A61K 35/17A61P 35/00A61K 40/15C12N 5/0646A61K 40/4224C12N 2501/2302C12N 2501/2315C12N 2501/22C12N 2501/2307C12N 2501/2306C12N 2501/60C12N 2501/125C12N 2501/145C12N 2501/26
62
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Claims

Abstract

Provided herein are methods of killing senescent cells, e.g., killing senescent cells in a human subject. Also provided herein are methods of treating a disease or disorder associated with cellular senescence in a subject in need thereof comprising administering to the subject an effective amount of placenta-derived NK cells to the subject. The present invention also provides compositions comprising NK, e.g., CYNK cells, for killing senescent cells and for the treatment of a disease or disorder associated with cellular senescence.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of killing senescent cells comprising contacting the senescent cells with placenta-derived natural killer (NK) cells. 
     
     
         2 . A method of treating a disease or disorder associated with cellular senescence in a subject in need thereof comprising administering to the subject an effective amount of placenta-derived NK cells to the subject so as thereby to provide an effective treatment of the disease or disorder in the subject. 
     
     
         3 . The method of  claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 20% CD56+CD3− natural killer cells. 
     
     
         4 . The method of  claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 40% CD56+CD3− natural killer cells. 
     
     
         5 . The method of  claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 60% CD56+CD3− natural killer cells. 
     
     
         6 . The method of  claim 1 or claim 2 , wherein the placenta-derived NK cells comprise at least 80% CD56+CD3− natural killer cells. 
     
     
         7 . The method of any of  claims 1-6 , wherein said placenta derived natural killer cells are human placenta derived natural killer cells. 
     
     
         8 . The method of any of  claims 1-6 , wherein said placenta derived natural killer cells are hematopoietic stem cell-derived natural killer cells. 
     
     
         9 . The method of any of  claims 1-6 , wherein said placenta derived natural killer cells are CD34+ hematopoietic stem cell-derived natural killer cells. 
     
     
         10 . The method of any of  claims 1-6 , wherein said placenta derived natural killer cells are CYNK cells. 
     
     
         11 . The method of any one of  claims 1-10 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS which is lower than expression of said markers in peripheral blood natural killer cells and/or expression of one or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 which is higher than expression of said markers in peripheral blood natural killer cells. 
     
     
         12 . The method of any one of  claims 1-11 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS which is lower than expression of said markers in peripheral blood natural killer cells. 
     
     
         13 . The method of  claim 12 , wherein expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more markers selected from the group consisting of FGFBP2, GZMH, CCL3L3, GZMM, CXCR4, ZEB2, KLF2, LITAF, RORA, LYAR, CNOT1, IFNG, DUSP2, ATG2A, CD7, PMAIP1, PPP2R5C, NR4A2, ZFP36L2, PIK3R1, KLRF1, SNHG9, MT2A, RGS2, CHD1, DUSP1, EML4, ZFP36, ZC3H12A, DNAJB6, SBDS, IRF1, TSC22D3, TSPYL2, PNRC1, ISCA1, JUNB, WHAMM, RICTOR, TNFAIP3, EPC1, MVD, CLK1, ARL4C, REL, KMT2E, YPEL5, AMD1, BTG2, and IDS is lower than expression of said markers in peripheral blood natural killer cells. 
     
     
         14 . The method of any one of  claims 1-13 , wherein the NK cells are characterized by expression of one or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 which is higher than expression of said markers in peripheral blood natural killer cells. 
     
     
         15 . The method of  claim 14 , wherein expression of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more markers selected from the group consisting of NDFIP2, LINC00996, MAL, CCL1, MB, SPINK2, C15orf48, CAMK1, KLRC1, TNFSF10, TNFRSF18, IL32, CAPG, AC092580.4, S100A11, TNFRSF4, ENO1, FCER1G, CCND2, KRT81, MRPS6, ANXA2, PTGER2, GLO1, HAVCR2, PYCARD, LAT2, SLC16A3, COTL1, PKM, TALDO1, CD96, NCR3, KRT86, STMN1, LTB, ARPC1B, ARPC5, FKBP1A, TIMP1, GZMK, CD59, PGK1, RGS10, EVL, RAC2, LGALS1, ITGB7, TUBB, PGAM1, PRF1, GZMB, IL2RB, KLRC2, and KLRB1 is higher than expression of said markers in peripheral blood natural killer cells. 
     
     
         16 . The method of any one of  claims 1-15 , wherein the NK cells are prepared by the methods presented herein. 
     
     
         17 . The method of any one of  claims 2-16 , wherein the disease or disorder is a fibrotic disease or disorder. 
     
     
         18 . The method of any one of  claims 2-16 , wherein the disease or disorder is a inflamatory disease or disorder. 
     
     
         19 . The method of any one of  claims 2-16 , wherein the disease or disorder is a metabolic disease or disorder. 
     
     
         20 . The method of any one of  claims 2-19 , wherein the disease or disorder is a liver disease or disorder. 
     
     
         21 . The method of any one of  claims 2-19 , wherein the disease or disorder is a kidney disease or disorder. 
     
     
         22 . The method of any one of  claims 2-19 , wherein the disease or disorder is a lung disease or disorder. 
     
     
         23 . The method of any one of  claims 2-19 , wherein the disease or disorder is a eye disease or disorder. 
     
     
         24 . The method of any one of  claims 2-19 , wherein the disease or disorder is a skeletal disease or disorder. 
     
     
         25 . The method of any one of  claims 2-19 , wherein the disease or disorder is a skin disease or disorder. 
     
     
         26 . The method of any one of  claims 2-19 , wherein the disease or disorder is a gastrointestinal disease or disorder. 
     
     
         27 . The method of any one of  claims 2-19 , wherein the disease or disorder is a bone marrow disease or disorder. 
     
     
         28 . The method of any one of  claims 2-19 , wherein the disease or disorder is a cardiovascular disease or disorder. 
     
     
         29 . The method of any one of  claims 2-19 , wherein the disease or disorder is a circulatory disease or disorder. 
     
     
         30 . The method of any one of  claims 2-19 , wherein the disease or disorder is a neuronal disease or disorder. 
     
     
         31 . The method of any one of  claims 2-19 , wherein the disease or disorder is an age-related disease or disorder. 
     
     
         32 . The method of any one of  claims 2-19 , wherein the disease or disorder is osteoarthritis. 
     
     
         33 . The method of any one of  claims 2-19 , wherein the disease or disorder is intervertebral disc degeneration. 
     
     
         34 . The method of any one of  claims 2-19 , wherein the disease or disorder is atherosclerosis. 
     
     
         35 . The method of any one of  claims 2-19 , wherein the disease or disorder is hardening of the arteries. 
     
     
         36 . The method of any one of  claims 2-19 , wherein the disease or disorder is heart disease. 
     
     
         37 . The method of any one of  claims 2-19 , wherein the disease or disorder is neurodegeneration. 
     
     
         38 . The method of any one of  claims 2-19 , wherein the disease or disorder is neuroinflammation. 
     
     
         39 . The method of any one of  claims 2-19 , wherein the disease or disorder is Alzheimer's disease. 
     
     
         40 . The method of any one of  claims 2-19 , wherein the disease or disorder is myeloproliferative neoplasm (MPN). 
     
     
         41 . The method of any one of  claims 2-19 , wherein the disease or disorder is myelodysplastic syndrome (MDS). 
     
     
         42 . The method of any one of  claims 2-19 , wherein the disease or disorder is osteoporosis. 
     
     
         43 . The method of any one of  claims 2-19 , wherein the disease or disorder is age-induced frailty. 
     
     
         44 . The method of any one of  claims 2-43 , wherein the effective treatment comprises a reduction in fibrosis. 
     
     
         45 . The method of any one of  claims 2-43 , wherein the effective treatment comprises a reduction in inflammation. 
     
     
         46 . The method of any one of  claims 2-43 , wherein the effective treatment comprises a reduction in senescent cell numbers. 
     
     
         47 . The method of any one of  claims 2-43 , wherein the effective treatment comprises a reduction in relative senescent cell numbers. 
     
     
         48 . The method of any one of  claims 2-43 , wherein the effective treatment comprises an increase in organ or tissue function. 
     
     
         49 . The method of  claim 1 , wherein the senescent cell is selected from the group consisting of a senescent fibroblast, a senescent pre-adipocyte, a senescent epithelial cell, a senescent chondrocyte, a senescent intervertebral disc cell, a senescent satellite cell, a senescent muscle cell, a senescent liver cell, a senescent kidney cell, a senescent liver cell, a senescent kidney cell, a senescent bone marrow cell, a senescent vascular cell, a senescent immune cell, a senescent heart cell, a senescent arterial cell, a senescent veinous cell, a senescent gastrointestinal cell, a senescent neuron, and a senescent endothelial cell. 
     
     
         50 . A composition comprising placenta-derived NK cells for use in killing senescent cells in a subject. 
     
     
         51 . Use of composition comprising placenta-derived NK cells for the manufacture of a medicament for killing senescent cells in a subject. 
     
     
         52 . A composition comprising placenta-derived NK cells for use treating a disease or disorder associated with cellular senescence in a subject.
 Use of a composition comprising placenta-derived NK cells for use treating a disease or disorder associated with cellular senescence in a subject.

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